Aralkyl carboxylic acid compounds

ABSTRACT

Novel compounds of the formulae ##STR1## wherein R represents lower alkyl or lower alkoxy, A represents --CH 2  --, --CO-- or ##STR2## n represents an integer of 1 to 8, X represents hydrogen or hydroxyl which may be protected and Y represents hydroxyl which may be protected, and their esters show an excellent action on the lysosomal membranes of cells, and exhibit excellent pharmacological activities such as physiologic host defense control activity, especially immuno-potentiating activity.

This invention relates to novel compounds of any of the formulae (I) to(IV) ##STR3## wherein R represents lower alkyl or lower alkoxy, Arepresents --CH₂ --, --CO-- or ##STR4## n represents an integer of 1 to8, X represents hydrogen or hydroxyl which may be protected and Yrepresents hydroxyl which may be protected, and their esters.

The present inventors have succeeded in synthesizing the novel compoundsof any of the formulae (I) to (IV) and found (1) that any of thecompounds (I) to (IV) have an excellent action on lysosomal membranes ofcells, and physiologic host defense control activity, especiallyimmuno-potentiating activity, and that accordingly these compounds areof use as medicaments for human or animal therapy; (2) that thesecompounds are invariably simple in chemical structure and suitable forindustrial production; (3) that these compounds have an adequate degreeof hydrophilicity and lend themselves conveniently to formulation intopharmaceutical products; and (4) that these compounds are comparativelystable against acid and light and can be employed advantageously asmedicaments.

The present invention has been accomplished on the basis of thesefindings.

Thus, the principal object of this invention is to provide the novelcompounds of any of the formulae (I) to (IV) and their esters useful asmedicines such as physiologic host defense control agents. Anotherobject of this invention is to provide an industrially feasible methodfor the production of these novel compounds, and a further object is toprovide pharmaceutical compositions comprising one or more of thesecompounds.

In any of the formulae (I) to (IV), the lower alkyl represented by R isadvantageously one having 1 to 4 carbon atoms, and is exemplified bymethyl, ethyl, n-propyl, i-propyl, n-butyl and i-butyl.

The lower alkoxy represented by R is advantageously one having 1 to 4carbon atoms, and is exemplified by methoxy, ethoxy, n-propoxy,i-propoxy, n-butoxy and i-butoxy. The integer represented by n isadvantageously 4 or 5 when R is lower alkyl, while the integer isadvantageously 1, 2, 7 or 8 when R is lower alkoxy.

As to the formulae (II) and (III), the protective group for the hydroxylX or Y may be any type of groups which can be easily removed and isexemplified by alkyl, aralkyl, acyl, acetal and silyl.

The alkyl of the protective group is advantageously one having up to 4carbon atoms and exemplified by methyl, ethyl, n-propyl, i-propyl,n-butyl and i-butyl. The aralkyl for the protective group isadvantageously benzyl.

As the acyl for the protective group, there may be mentioned alkylcarbonyl, aryl carbonyl, aralkyl carbonyl, especially alkyl carbonylhaving 1 to 4 carbon atoms such as acetyl, n-propionyl and n-butyryl.The acetal for the protective group is advantageouslyα-tetrahydropyranyl or methoxymethyl.

As the silyl for the protective group, trimethylsilyl is usedadvantageously.

Referring to the formulae (I) and (II), the type of ester isadvantageously alkyl ester, aryl ester or aralkyl ester, the alkyl, aryland aralkyl moieties of which may be substituted.

The alkyl moiety of the alkyl ester is advantageously one having up to 4carbon atoms and exemplified by methyl, ethyl, n-propyl, i-propyl,n-butyl and i-butyl. The aryl moiety of the aryl ester is advantageouslyone having up to 7 carbon atoms and exemplified by phenyl and p-tolyl.The aralkyl moiety of the aralkyl ester is advantageously one having upto 8 carbon atoms and exemplified by benzyl and phenethyl.

The substituent of these moieties may be sulfo, carboxyl, formyl,hydroxyl or/and amino.

Referring to the formulae (III) and (IV), the type of ester isadvantageously alkyl carboxylic acid ester, aryl carboxylic acid esteror aralkyl carboxylic acid ester, the alkyl, aryl and aralkyl moietiesof which may be substituted.

As the alkyl, aryl and aralkyl moieties and the substituents of thesemoieties, those mentioned above in connection with the esters of thecompounds (I) and (II) may be mentioned.

The compounds of the formulae (I) to (IV) may be produced by, forexample, the processes schematically shown and explained in detailbelow: ##STR5##

The group of compounds (I), (II), (III) and (IV) may all be synthesizedstarting from the compound (VII), ##STR6## wherein R, X and Y have thesame meaning as defined above, which is a known compound, and some ofthe compounds included in this group may be synthesized starting from acompound (V) ##STR7## wherein R has the same meaning as defined above,which is also a known compound.

Namely, when the compound (VII) is employed for the starting compound,it is first converted into the compound (II-1) ##STR8## wherein R, n, Xand Y have the same meaning as defined above, which is one of the objectcompounds, and then the latter may further be converted into othercompounds through various synthetic means. On the other hand, when thecompound (V) is selected as the starting material, one may directlysynthesize the compound (I-2) ##STR9## wherein R and n have the samemeaning as defined above, which is one of the objective compounds, andthen the latter may be changed into the compound (II-2).

The processes for producing the compounds (I), (II), (III) and (IV),namely the steps (1) to (18), will be more particularly mentioned below:

Step (1)

In the step (1), a compound (VII) is reacted with a compound of theformula (VIII) ##STR10## wherein n has the same meaning as definedabove, or a compound of the formula (IX) ##STR11## wherein Z representscarboxyl which may be esterified, Hal represents halogen atom and n hasthe same meaning as defined above, to obtain the compounds (II-1). Inthis reaction it is advantageous to employ a catalyst.

As the catalyst, any catalysts employed in the Friedel-Crafts Reaction,for example, sulfonic acid, phosphoric acid, poly phosphoric acid, andLewis acids such as aluminum chloride are employed. While this reactionadvances in the absence of a solvent, it is usually conducted in thepresence of an inert solvent such as nitrobenzene, carbon disulfide, ortetrachloroethane. The reaction temperature is advantageously about 50°C.-150° C.

Step (2)

In the step (2), a compound (II-1) is oxidized to obtain the compounds(I-1).

This oxidation is performed by a procedure which is conventional. Anyoxidation procedure by which phenol may be converted to quinone can beemployed with advantage. The preferred oxidizing agents are ferricchloride, silver oxide, manganese dioxide, hydrogen peroxide, peraceticacid, performic acid, perbenzoic acid, potassium permanganate, potassiumnitrosodisulfonate, and potassium dichromate.

This oxidation is generally conducted in a suitable solvent. Any solventthat does not intefere with this oxidation may be employed for thispurpose; thus, for example, water, a dilute aqueous solution of an acidor an alkali, acetone, ethanol, dioxane, ether, acetic acid and so onmay be mentioned. The progress of the reaction may be monitored bythin-layer chromatography. For such detection purpose, a yellow spot, apositive reaction to leucomethylene blue or ultraviolet absorptionspectrometry may be employed.

While the reaction temperature and time are dependent to a certainextent upon the type of oxidizing agent, generally preferred conditionsare about 0° C. to 25° C. and about 0.5 to 5 hours. Satisfactory resultsare also obtained when the reaction is conducted in a suitable buffersolution (e.g. phosphate buffer).

Step (3)

In the step (3), a compound (II-1) is reduced to obtain the compound(II-2).

The procedure for this reduction may be any procedure by which thecarbonyl of the compounds (II-1) may be converted to a methylene. Assuch procedures, there may be mentioned Clemmensen reduction,Wolff-Kishner reduction, a method comprising converting the startingcompound to the dithioacetate and reducing the latter throughdesulfuration, and catalytic reduction. Generally, this reaction isadvantageously conducted in the presence of a suitable solvent. Thesolvent may be any solvent that does not interfere with the reaction,being exemplified by ether, methanol, ethanol, benzene, toluene, xylene,ethylene glycol, triethylene glycol, acetic acid and so on. Theaforementioned reduction reactions may each be easily carried out in theroutine manner.

Step (4)

In the step (4), a compound (II-2) is oxidized to obtain the compounds(I-2). This oxidation is performed by the same means as those set forthin the step (2).

Step (5)

In the step (5), a compound (II-1) is reduced to obtain the compounds(II-3).

The procedure for this reduction may be any procedure by which ketonemay be converted to alcoholic hydroxyl without effecting the carboxyl,thus being exemplified by catalytic reduction, reduction by means ofreducing agents such as sodium borohydride.

Step (6)

In the step (6), a compound (II-3) is oxidized to obtain the compounds(I-3).

The procedure for this oxidation may be any procedure by which phenolmay be converted to quinone without affecting the alcoholic hydroxyl.The oxidizing agent is advantageously ferric chloride, silver oxide orpotassium nitrosodisulfonate.

This oxidation is performed under conditions similar to those set forthin the step (2).

Step (7)

In the step (7), a compound (I-1) is reduced to obtain the compounds(II-2).

As for the procedures of reduction, those mentioned hereinbefore inconnection with the step (3) may be employed. In this step, thecompounds (II-2) wherein X and Y are hydroxyl are obtained.

Step (8)

In the step (8), a compound (I-1) is reduced to obtain the compounds(II-1). This reduction may be accomplished by any procedure by whichquinone can be converted to hydroquinone without affecting the carbonyl.Thus, for example, reduction by means of a hydrosulfite may be employedwith advantage. In this step, the compounds (II-1) wherein X and Y arehydroxyl are obtained.

Step (9)

In the step (9), a compound (V) is reacted with a peroxide of acarboxylic acid of the formula (IX)

    z--(ch.sub.2).sub.n+1 --COOH                               (VI)

wherein n and Z have the same meaning as defined above or of itsanhydride.

The aforementioned peroxide of the carboxylic acid (VI) or of ananhydride thereof may be any compound that, when heated, gives rise toan alkyl radical with the evolution of carbon dioxide, and can beobtained by permitting a peroxide (e.g. hydrogen peroxide, a metal saltthereof, lead tetraacetate, etc.) to act upon the carboxylic acid or anacid halide or acid anhydride thereof.

The reaction of this step is advantageously conducted in a suitableinert solvent such as, n-hexane, ligroine, toluene, xylene, acetic acidor propionic acid. The reaction temperature is advantageously in therange of about 80° C. to 100° C., and the reaction time is desirably inthe range of about 0.5 to 3 hours. This reaction proceeds with theevolution of carbon dioxide under very mild conditions, accompanied onlyby a minimum of side reaction, enabling the desired product to beproduced in satisfactory yield and, after the reaction, the unreactedstarting material to be completely recovered.

The present reaction may also be conducted under conditions such thatthe aforesaid peroxide is produced in the reaction system. For example,the compound (V) may be reacted with a carboxylic acid of formula (VI)or its anhydride in the presence of a tetravalent lead compound (e.g.lead tetraacetate). This reaction is advantageously carried out in asuitable inert solvent (e.g. n-hexane, ligroine, toluene, xylene, aceticacid, propionic acid, etc.), the reaction temperature being desirablymaintained in the range of 50° C. to 150° C.

Step (10)

In the step (10), a compound (I-2) is reduced to obtain the compounds(II-2). The reduction procedure may be any procedure by which quinonemay be converted to hydroquinone, thus being exemplified by catalyticreduction, reduction by means of a hydrosulfite, etc., which may beemployed with advantage. In this step the compounds (II-2), wherein Xand Y are hydroxyl are obtained.

Step (11)

In the step (11), a compound (II-1) is reduced to obtain the compounds(III-3). The procedure for this reduction may be any procedure by whichcarboxyl may be converted to an alcoholic hydroxyl. As such procedures,there may be mentioned reduction by means of lithium aluminum hydride.Generally this reduction is advantageously conducted in the presence ofa suitable solvent. The solvent may be any solvent that does notintefere with the reduction being exemplified by ethers (e.g. diethylether, tetrahydrofuran, dioxane).

Step (12)

In the step (12), a compound (III-3) is reduced to obtain the compounds(III-2). The procedure for this reduction may be any procedure by whichalcoholic hydroxyl may be converted to hydrogen. The reduction may becarried out by per se known reduction means. Thus catalytic reductionmay be employed with advantage. As the catalyst, palladium, platinumoxide or the like may be advantageously employed. Generally, thisreduction is advantageously conducted in the presence of a suitablesolvent. The solvent may be any solvent that does not interfere with thereduction, being exemplified by acetic acid and alcohols (e.g. methanol,ethanol). This reduction may be advantageously conducted in the presenceof for example, an acid (e.g. hydrochloric acid, perchloric acid etc.).

Step (13)

In the step (13), a compound (III-2) is oxidized to obtain the compounds(IV-2). The procedure for this oxidation may be any procedure by whichphenol may be converted to quinone without affecting the hydroxyl. Theoxidizing agent is advantageously ferric chloride, silver oxide,nitrosodisulfonate and so on.

This oxidation is generally conducted in a suitable solvent. Any solventthat does not intefere with this oxidation may be employed for thispurpose; thus, for example, water, a dilute aqueous solution of an acidor an alkali, acetone, ethanol, dioxane, ether, acetic aciddimethylformamide and so on may be mentioned.

While the reaction temperature and time are dependent to a certainextent upon the type of oxidizing agent, generally preferred conditionsare about 0° C. to 25° C. and about 0.5 to 5 hours.

Step (14)

In the step (14), a compound (III-3) is oxidized to obtain the compounds(IV-3). This oxidation is performed by procedures similar to those setforth in the step (13).

Step (15)

In the step (15), a compound (IV-3) is oxidized to obtain the compounds(IV-1). This oxidation is advantageously conducted after protecting the--CH₂ OH group in a compound (IV-3). The protective group may be anytype of group which can be easily removed and is exemplified by acyl(e.g. acetyl, benzyl, benzoyl, etc.), acetal (tetrahydropyranyl etc.).The preferred oxidizing agents are manganese dioxide and chromiumtrioxide.

Step (16)

In the step (16), a compound (IV-1) is reduced to obtain the compounds(III-1). This reduction is performed by procedures similar to those setforth in the step (8). In this step. the compounds (III-1) wherein X andY are hydroxyl are obtained.

Step (17)

In the step (17), a compound (III-1) is oxidized to obtain the compounds(IV-1). This oxidation is performed by procedures similar to those setforth in step (13).

When the compounds (I) and (II) thus obtained have free carboxyl, thesecompounds can be esterified by a procedure known per se to the compounds(I) and (II) having esterified carboxyl.

Step (18)

In the step (18), a compound (I-2) is reduced to obtain the compounds(III-2). This reduction is performed by procedures similar to those setforth in the step (11).

To accomplish the aforementioned esterification, there may for instancebe employed the technique which comprises reacting a compound (I), (II)or a reactive derivative thereof at their carboxyl function with analcohol, phenol compound, alkyl halide, aralkyl halide or dialkylsulfate or diazomethane, for instance. As the reactive derivatives ofcarboxylic acids, there may be mentioned the carboxylic anhydrides,carboxylic halides, metal carboxylate (e.g. sodium, potassium, silverand other salts of carboxylic acids) and so on. The alcohol may forexample be methanol, ethanol, n-propanol, isopropanol, n-butanol,isobutanol, etc.; the alkyl halides are methyl iodide, ethyl iodide,benzyl chloride and so on.

Among the compounds (I) and (II), the compounds (I-3) and (II-3) can beesterified also at their ##STR12## by procedures similar to thosementioned hereinafter in connection with the esterification of thecompounds (III) and (IV).

When the compounds (I) and (II) thus obtained have esterified carboxyl,these compounds can be converted to the compounds (I) and (II) havingfree carboxyl by a hydrolytic procedure which is known per se.

The above hydrolysis is conducted with advantage in the presence of, forexample, a mineral acid (e.g. sulfuric acid, hydrochloric acid) or analkaline substance (e.g. sodium hydroxide, potassium hydroxide, calciumhydroxide).

Further, the hydrolysis reaction is conducted with advantage in thepresence of suitable antioxidant (e.g. pyrogallol etc.) or reducingagent (e.g. hydrosulfite, etc.).

Among the compounds (I) and (II), the compound (I-3) and (II-3), havingesterified alcoholic hydroxyl can be coverted to the compound (I-3) and(II-3) having hydroxyl by procedures similar to those mentionedhereinbefore.

When the compounds (III) and (IV) thus obtained have alcoholic hydroxyl,the compounds can be esterified by a procedure known per se to thecompounds (III) and (IV) having esterified alcoholic hydroxyl.

To accomplish the esterification, there may for instance be employed themethod which comprises reacting the compound (III) or (IV) havingalcoholic hydroxyl with carboxylic acid compound or a reactivederivative thereof. As the carboxylic acid there may be mentioned thealkyl carboxylic acid, aryl carboxylic acid, aralkyl carboxylic acid. Asthe reactive derivatives of the carboxylic acids, there may be mentionedthe carboxylic anhydrides, carboxylic halides, carboxylic acid loweralcohol esters, metal carboxylate and so on.

In the case of the compounds (III-3) and (IV-3), generally thisesterification would occur at the --CH₂ OH and ##STR13## groups, but itis possible to esterify at the --CH₂ OH group alone by the selection ofconditions, such as that the ratio of the compounds (III-3) or (IV-3) tothe carboxylic acid or its reactive derivative is adjusted 1 to 1.

When the compounds (III) and (IV) thus obtained have esterifiedalcoholic hydroxyl, the compounds can be converted to the compound (III)and (IV) having alcoholic hydroxyl by a hydrolytic procedure which issimilar to those set forth in connection with the compounds (I).

Thus obtained compounds (I) to (IV) can be easily isolated by proceduresknown per se, such as pH adjustment, phasic transfer, concentration,distillation under reduced pressure, chromatography, crystallization,recrystallization and the like.

In the case of the compounds (I) and (II) having free carboxyl, thesecompound may be isolated either as the free carboxylic acid or in theform of a pharmaceutically acceptable salt.

These free carboxylic acids may, after being isolated, be converted to apharmaceutically acceptable salt. The pharmaceutically acceptable saltmentioned above is exemplified by metal salts such as alkali metalsalts, e.g. sodium and potassium salt, alkaline earth metal salts, e.g.magnesium and calcium, aluminum salts, and amine salts, e.g. ammonium,trimethylamine and triethylamine salts.

The compounds (I) and their salts thus obtainable are novel and havephysiologic host defense control action, especially immuno-potentiatingaction; smooth muscle relaxant action; and other action, and accordinglythese compounds are of use, for example, as physiologic host defensecontrol agents, especially immuno-potentiating agents for mammalsincluding human beings.

Among the compounds (I), the compounds (I-1) can be used also as theintermediate for producing the compound (I-2).

Further, among the compounds (I), the compounds (I-2) wherein R is loweralkyl and a compound (I-2) wherein R is lower alkoxy and n is not lessthan 3 have excellent action to stabilize the lysosomal membranes ofcells; and the compounds (I-2) wherein R is lower alkoxy and n is notmore than 2 have excellent action to labilize the lysosomal membranes ofcells.

Furthermore the compounds (I-1) and (I-3) also have excellent action tothe lysosomal membranes of cells.

The compounds (I) and their salts are administered orally or non-orallyto mammals including human beings, either by themselves or in admixturewith a suitable carrier, for example in such dosage forms as powders,granules, tablets and injections.

Pharmaceutical compositions containing one or more of the compounds (I)and their salts can be prepared by per se conventional methods for thepreparation of powder, capsules, tablets, granules, injections, and thelike. The choice of carriers may be determined depending upon the routeof administration, the solubility of the compounds and so on.

While the dosage of the compounds (I) may be chosen depending upon thespecies of host, the purpose of administration and the route ofadministration, when used as immuno-potentiating agents for mammals, forinstance, the preferred parental dose is about 50 μg-50 mg./kg.,advantageously 1-25 mg/kg., per injection.

The compounds (II) and their salts, (III) and (IV) thus obtainable arenovel, and also have physiologic host defense control action; action tolysosomal membranes of cells and so on similar to those set forth inconnection with the compounds (I), and, as such, can be use as medicinesin the same manner as the compounds (I).

Further, the compounds (II) can be used also as intermediates forproducing the compounds (I).

The following Examples are intended merely to illustrate presentlypreferred embodiments of the present invention and not to restrict thescope of this invention.

Throughout the foregoing description as well as in the followingExamples and Claims, "μg.", "mg.", "kg.", "ml.", "° C" and "N"respectively refer to "microgram(s)", "milligram(s)", "kilogram(s)","milliliter(s)", "degrees centrigrade" and "Normal(s)". The word"part(s)" is based on weight unless otherwise noted and the relationshipbetween "part(s)" and "volume part(s)" corresponds to that between"gram(s)" and "milliliter(s)".

EXAMPLE 1

(1) To a solution of 2,3,5-trimethylphenol(formula VII wherein R=H₃ C,X=H, Y=OH) (1.4 part) in tetrachloroethane (10 volume parts), there wasadded a solution of aluminum chloride dust (3.5 parts) and ethyl5-chloroformylpentanoate (3 parts) in tetrachloroethane (5 volume parts)at 0° C. and in a current of nitrogen gas and the mixture was heated at110°-120° C. for 17 hours. To the reaction mixture was added cold water(50 volume parts) and the dilution was acidified with dilutehydrochloric acid and extracted with chloroform (200 volume parts). Theresidue (2.7 parts) obtained from the extract was subjected to columnchromatography on silicic acid (60 parts) and eluted withchloroform-diethyl ether (20:1) (300 volume parts). The eluate wasevaporated to dryness and the residue was recrystallized from ethanol.The procedure provided colorless needles of ethyl5-(2'-hydroxy-3',4',6'-trimethylbenzoyl)pentanoate (formula II-1 whereinR=H₃ C, X=H, Y=OH, n=4, in the form of ethyl ester) (1.9 part) meltingat 72°-73° C.

Infrared absorption spectrum ν_(max) ^(KBr) cm⁻¹ : 3450(OH), 1720(COOC₂H₅), 1610(CO).

Nuclear magnetic resonance spectrum (τ in deuterochloroform): 8.76(CH₃,triplet), 8.5-8.1(CH₂, multiplet), 8.0-7.6 (CH₂, multiplet), 7.89(ringCH₃, singlet), 7.78(ring CH₃, singlet), 7.50(ring CH₃, singlet),7.25-7.00 (CH₂, multiplet), 5.88(OCH₂, quartet), 3.48(ring proton,singlet).

Elemental analysis, C₁₇ H₂₄ O₄ -- Calculated: C, 69.83; H, 8.27. Found:C, 69.78; H, 8.44.

(2) To a solution of the above product (0.61 part) in aqueous acetone(acetone-water=5:1)(12 volume parts) was added dropwise a 10% aqueoussolution of sodium hydroxide (10 volume parts) under stirring at roomtemperature. After stirring for 30 minutes, the reaction mixture wascooled to 0° C. and cold water (50 volume parts) was added. The dilutionwas rendered acidic with cold dilute hydrochloric acid and the resultantwhite precipitate was recrystallized from ethanol. The procedureprovided colorless needles of5-(2'-hydroxy-3',4',6'-trimethylbenzoyl)pentanoic acid (formula II-1wherein R=H₃ C, X=H, Y=OH, n=4, in the free form) (0.428 part) meltingat 146°-148° C.,

Infrared absorption spectrum ν_(max) ^(KBr) cm⁻¹ : 3430(OH), 1700(COOH),1605(CO).

Nuclear magnetic resonance spectrum (τ in deuterochloroform):8.5-8.0(CH₂, multiplet), 8.0-7.3(CH₂, multiplet), 7.88(ring CH₃,singlet), 7.78(ring CH₃, singlet), 7.47(ring CH₃, singlet), 7.2-6.9(CH₂,multiplet), 3.47(ring proton, singlet).

Elemental analysis, C₁₅ H₂₀ O₄ -- Calculated: C, 68.16; H, 7.63. Found:C, 67.95; H, 7.92.

EXAMPLE 2

(1) 2,3,5-Trimethylphenol (formula VII wherein R=H₃ C, X=H, Y=OH)(0.9part), aluminum chloride (2.1 parts) and ethyl 6-chloroformylhexanoate(1.3 part) were treated as in Example 1 (1). The procedure providedcolorless needles of ethyl6-(2'-hydroxy-3',4',6'-trimethylbenzoyl)hexanoate (formula II-1 whereinR=H₃ C, X=H, Y=OH, n=5, in the form of ethyl ester) (1.5 part) meltingat 47°-48° C.

Infrared absorption spectrum ν_(max) ^(KBr) cm⁻¹ : 1735(COOC₂ H₅),1610(CO).

Nuclear magnetic resonance spectrum (τ in deuterochloroform): 8.76(CH₃,triplet), 8.7-8.0(CH₂, multiplet), 8.0-7.4(CH₂, multiplet), 7.88(ringCH₃, singlet), 7.78(ring CH₃, singlet), 7.49(ring CH₃, singlet),7.01(CH₂, triplet), 5.87(OCH₂, quartet), 3.47(ring proton, singlet).

Elemental analysis, C₁₈ H₂₆ O₄ -- Calculated: C, 70.56; H, 8.55. Found:C, 70.23; H, 8.72.

(2) By a procedure similar to that described in Example 1 (2), the aboveproduct (1 part) was hydrolyzed to obtain colorless needles of6-(2'-hydroxy-3',4',6'-trimethylbenzoyl)hexanoic acid (formula II-1wherein R=H₃ C, X=H, Y=OH, n=5, in the free form)(0.8 part) which meltedat 119°-125° C.

Infrared absorption spectrum ν_(max) ^(KBr) cm⁻¹ : 1710(COOH), 1610(CO).

Nuclear magnetic resonance spectrum (τ in deuterochloroform):8.7-8.0(CH₂, multiplet), 8.0-7.3(CH₂, multiplet), 7.86(ring CH₃,singlet), 7.75(ring CH₃, singlet), 7.47(ring CH₃, singlet), 7.06(CH₂,triplet), 3.46 ring proton, singlet)

Elemental analysis, C₁₆ H₂₂ O₄ -- Calculated: C, 69.04; H, 7.97. Found:C, 69.12; H, 7.75.

EXAMPLE 3

(1) 2,3,5-Trimethylphenol (formula VII wherein R=H₃ C, X=H, Y=OH)(1.5part), aluminum chloride (3.5 parts) and ethyl 9-chloroformylnonanoate(3 parts) were treated together in the same manner as Example 1 (1).

The procedure provided ethyl9-(2'-hydroxy-3',4',6'-trimethylbenzoyl)nonanoate (formula II-1 whereinR=H₃ C, X=H, Y=OH, n=8, in the form of ethyl ester) as colorless needles(2 parts) melting at 48°-50° C.

Infrared absorption spectrum ν_(max) ^(KBr) cm⁻¹ : 3450(OH), 1735(COOC₂H₅), 1610(CO).

Nuclear magnetic resonance spectrum(τ in deuterochloroform):9.0-8.0(CH₂, multiplet), 8.76(CH₃, triplet), 8.0-7.4(CH₂, multiplet),7.88(ring CH₃, singlet), 7.78(ring CH₃, singlet), 7.49(ring CH₃,singlet), 7.04(CH₂, triplet), 5.87(OCH₂, quartet), 3.47(ring proton,singlet).

Elemental analysis, C₂₁ H₃₂ O₄ -- Calculated: C, 72.38; H, 9.26. Found:C, 72.32; H, 9.56.

(2) The above product (1.4 part) was hydrolyzed in the same manner asExample 1 (2). The procedure provided9-(2'-hydroxy-3',4',6'-trimethylbenzoyl)nonanoic acid (formula II-1wherein R=H₃ C, X=H, Y=OH, N=8, in the free form) as colorless needles(1.2 part) melting at 97°-100° C.

Infrared absorption spectrum ν_(max) ^(KBr) cm⁻¹ : 3450(OH), 1710(COOH),1610(CO).

Nuclear magnetic resonance spectrum (τ in deuterochloroform):8.9-8.0(CH₂, multiplet), 8.0-7.3(CH₂, multiplet), 7.85(ring CH₃,singlet), 7.77(ring CH₃, singlet), 7.47(ring CH₃, singlet), 7.07(CH₂,triplet), 3.45(ring proton, singlet).

Elemental analysis, C₁₉ H₂₈ O₄ -- Calculated: C, 71.22; H, 8.81. Found:C, 71.10; H, 8.97.

EXAMPLE 4

(1) Under cooling with ice, aluminum chloride (4.08 parts) was added insmall portions to a mixed solution of ethyl 9-chloroformylnonanoate(3.52 parts) and 3,4,5-trimethoxytoluene(formulaVII wherein R=H₃ CO,X=H, Y=H₃ CO) (2.21 parts) in nitrobenzene (20 volume parts). Themixture was stirred at 0° C. for 16 hours and, then, at room temperaturefor 1.5 hours. The reaction mixture was rendered acidic with dilutehydrochloric acid and extracted with diethyl ether. By a proceduresimilar to that described in Example 1 (2), the extract was hydrolyzedand subjected to column chromatography on silicic acid. The fractioneluted by benzenediethyl ether (9:1) yielded9-(2',3',4'-trimethoxy-6'-methylbenzoyl)nonanoic acid (formula II-1wherein R=H₃ CO, X=H, Y=OCH₃, n=8, in the free form) (1.82 part). Fromthe fraction eluted by benzene-diethyl ether (5.7:1), there was obtained9-(2'-hydroxy-3',4'-dimethoxy-6'-methylbenzoyl)nonanoic acid (formulaII-1, R=H₃ CO, X=H, Y=OH, n=8, in the free form) (0.67 part) ascolorless needles melting at 75°-76.5° C.

Elemental analysis, C₁₉ H₂₈ O₆ -- Calculated: C, 64.75; H, 8.01. Found:C, 64.87; H, 8.06.

EXAMPLE 5

3,4,5-Trimethoxytoluene(formula VII wherein R=H₃ CO, X=H, Y=H₃ CO)(2.09parts) and ethyl 5-chloroformylpentanoate (2.66 parts) were treated inthe same manner as Example 4. The procedure provided5-(2'-hydroxy-3',4'-dimethoxy-6'-methylbenzoyl)pentanoic acid (formulaII-1 wherein R=H₃ CO, X=H, Y=OH, n=4, in the free form)(1.97 part) aspale-brown needles melting at 111°-112° C.

Infrared absorption spectrum ν_(max) ^(KBr) cm⁻¹ : 3250(OH), 1740(COOH),1615(CO).

Elemental analysis, C₁₅ H₂₀ O₆ -- Calculated: C, 60.80; H, 6.80. Found:C, 60.69; H, 6.75.

EXAMPLE 6

3,4,5-Trimethoxytoluene (formula VII wherein R=H₃ CO, X=H, Y=H₃ CO)(3.65 parts) and succinic anhydride (2.4 parts) were dissolved in amixture of nitrobenzene (10 volume parts) and tetrachloroethane (30volume parts) and, under cooling with ice and stirring. To the mixture,aluminum chloride dust (7.2 parts) was added in small portions. Themixture was allowed to stand at room temperature for 4 days and,following the addition of dilute hydrochloric acid, it was extractedwith diethyl ether. The ethereal layer was then extracted with a 10%solution of sodium carbonate. The sodium carbonate extract was washedwith diethyl ether to remove the nitrobenzene and tetrachloroethane andthe water layer was rendered acidic with dilute hydrochloric acid. Theresulting oil precipitate was extracted with ethyl acetate, washed withwater and dried. The solvent was distilled off under reduced pressure.

The residue was then recrystallized from methanol, whereupon3-(2'-hydroxy-3',4'-dimethoxy-6'-methylbenzoyl)propionic acid (formulaII-1 wherein R=H₃ CO, X=H, Y=OH, n=2, in the free form) (1 part) wasobtained as pale-yellowish crystals melting at 145°-147° C.

Elemental analysis, C₁₃ H₁₆ O₆ --

Calculated: C, 58.20; H, 6.01. Found: C, 58.07; H, 5.98.

EXAMPLE 7

To 5-(2'-hydroxy-3',4',6'-trimethylbenzoyl)pentanoic acid (formula II-1wherein R=H₃ C, X=H, Y=OH, n=4, in the free form) (0.262 part) wereadded water (16 volume parts), toluene (20 volume parts), concentratedhydrochloric acid (4 volume parts) and zinc amalgam prepared from 2parts of zinc. The mixture was refluxed for 16 hours, during which timeconcentrated hydrochloric acid (6 volume parts) was added in threeportions. After cooling, the reaction mixture was diluted with water andextracted with diethyl ether. The extract was washed with water anddried. The solvents were distilled off under reduced pressure to obtain6-(2'-hydroxy-3',4',6'-trimethylphenyl)hexanoic acid (formula II-2wherein R=H₃ C, X=H, Y=OH, n=4, in the free form)(0.251 part) ascolorless needles melting at 96°-108° C.

Infrared absorption spectrum ν_(max) ^(KBr) cm⁻¹ : 3400(OH), 1700(COOH).

Nuclear magnetic resonance spectrum (τ in deuterochloroform):8.8-8.0(CH₂, multiplet), 7.9-7.2(CH₂, multiplet), 7.90(ring CH₃,singlet), 7.80(ring CH₃, singlet), 3.41(ring proton, singlet).

Elemental analysis, C₁₅ H₂₂ O₃ -- Calculated: C, 71.97; H, 8.86. Found:C, 71.67; H, 9.02.

EXAMPLE 8

6-(2'-Hydroxy-3',4',6'-trimethylbenzoyl)hexanoic acid (formula II-1wherein R=H₃ C, X=H, Y=OH, n=5, in the free form) (0.326 part) wasreduced by a procedure similar to that described in Example 7. Theprocedure provided 7-(2'-hydroxy-3',4',6'-trimethylphenyl)heptanoic acid(formula II-2 wherein R=H₃ C, X=H, Y=OH, n=5, in the free form) (0.25part) as colorless needles melting at 91°-104° C.

Infrared absorption spectrum ν_(max) ^(KBr) cm⁻¹ : 3450(OH), 1710(COOH).

Nuclear magnetic resonance spectrum (τ in deuterochloroform):8.9-8.1(CH₂, multiplet), 8.0-7.2(CH₂, multiplet), 7.87(ring CH₃,singlet), 7.78(ring CH₃, singlet), 3.42(ring proton, singlet).

Elemental analysis, C₁₆ H₂₄ O₃ -- Calculated: C, 72.69; H, 9.15. Found:C, 72.48; H, 9.08.

EXAMPLE 9

9-(2'-Hydroxy-3',4',6'-trimethylbenzoyl)nonanoic acid (formula II-1wherein R=H₃ C, X=H, Y=OH, n=8, in the free form) (1.1 part) was reducedand treated by a procedure similar to that described in Example 7. Theprocedure provided 10-(2'-hydroxy-3',4',6'-trimethylphenyl)decanoic acid(formula II-2 wherein R=H₃ C, X=H, Y=OH, n=8, in the free form) (0.4part) as a colorless oil.

EXAMPLE 10

9-(2'-Hydroxy-3',4'-dimethoxy-6'-methylbenzoyl)nonanoic acid (formulaII-1, wherein R=H₃ CO, X=H, Y=OH, n=8, in the free form) (0.254 part),zinc amalgam (0.56 part), toluene (1 volume part), 35% hydrochloric acid(0.5 volume part) and a small proportion of water were refluxed for 5hours. The toluene layer was separated and the water layer was extractedwith diethyl ether. The toluene layer was combined with the ethereallayer, washed with water and dried. The solvents were then distilled offunder reduced pressure and the residue was recrystallized from ligroine.The foregoing procedure provided10-(2'-hydroxy-3',4'-dimethoxy-6'-methylphenyl)decanoic acid (formulaII-2 wherein R=H₃ CO, X=H, n=8, in the free form) (0.14 part) ascolorless powdery crystals melting at 62.5°-66° C.

Nuclear magnetic resonance spectrum (τ in deuterochloroform):8.80-8.13(CH₂, multiplet), 7.78(ring CH₃, singlet), 7.57(COCH₂, CH₂ CO,triplet), 6.20(OCH₃, singlet), 6.16(OCH₃, singlet), 4.77(ring proton,singlet).

Elemental analysis, C₁₉ H₃₀ O₅ -- Calculated: C, 67.43; H, 8.94. Found:C, 67.50; H, 8.89.

EXAMPLE 11

5-(2'-Hydroxy-3',4'-dimethoxy-6'-methylbenzoyl)pentanoic acid (formulaII-1 wherein R=H₃ CO, X=H, Y=OH, n=4, in the free form) (1.49 part) wasreduced and treated by a procedure similar to that described in Example10. The procedure provided6-(2'-hydroxy-3',4'-dimethoxy-6'-methylphenyl)hexanoic acid (formulaII-2 wherein R=H₃ CO, X=H, Y=OH, n=4, in the free form) (0.6 part) ascolorless crystals melting at 38°-44° C.

Elemental analysis, C₁₅ H₂₂ O₅ -- Calculated: C, 63.81; H, 7.85. Found:C, 63.54; H, 7.70.

EXAMPLE 12

A mixture of 3-(2'-hydroxy-3',4'-dimethoxy-6'-methylbenzoyl)propionicacid (formula II-1 wherein R=H₃ CO, X=H, Y=OH, n=2 in the free form)(0.536 part), zinc amalgam (1 part), concentrated hydrochloric acid (1volume part), water (2 volume parts) and toluene (2 volume parts) wasrefluxed for 5 hours and, after cooling, the reaction mixture wasextracted with diethyl ether. The extract was washed with water anddried. The solvents were distilled off under reduced pressure and theresidue was recrystallized from diethyl ether-hexane. The procedureprovided 4-(2'-hydroxy-3',4'-dimethoxy-6'-methylphenyl)butyric acid(formula II-2 wherein R=H₃ CO, X=H, Y=OH, n=2, in the free form) (0.34part) as colorless needles melting at 98°-100° C.

Elemental analysis, C₁₃ H₁₈ O₅ -- Calculated: C, 61.40; H, 7.14. Found:C, 61.35; H, 7.01.

EXAMPLE 13

9-(2'-Hydroxy-3',4'-dimethoxy-6'-methylbenzoyl)nonanoic acid (formulaII-1 wherein R=H₃ CO, X=H, Y=OH, n=8, in the free form) (0.197 part) wasdissolved in methanol saturated with hydrogen chloride gas (7 volumeparts) and the solution was stirred at room temperature for 20 minutes.The methanol was distilled off under reduced pressure and the residuewas recrystallized from hexane-diethyl ether. The procedure providedmethyl 9-(2'-hydroxy-3',4'-dimethoxy-6'-methylbenzoyl)nonanoate (formulaII-1 wherein R=H₃ CO, X=H, Y=OH, n=8, in the form of methyl ester)(0.195 part) as colorless needles melting at 49°-53° C.

Infrared absorption spectrum ν_(max) ^(KBr) cm⁻¹ : 1740(COOCH₃),1620(CO).

Nuclear magnetic resonance spectrum(τ in deuterochloroform):8.82-8.13(CH₂, multiplet), 7.68(CH₂ CO, triplet), 7.57(CH₃, singlet),7.10(COCH₂, triplet), 6.33(COOCH₃, singlet), 6.15(OCH₃, singlet), 6.10(OCH₃, singlet), 3.67(ring proton, singlet), -0.03 (OH, singlet).

Elemental analysis, C₂₀ H₃₀ O₆ -- Calculated: C, 65.55; H, 8.25. Found:C, 65.58; H, 8.17.

EXAMPLE 14

A solution of methyl9-(2'-hydroxy-3',4'-dimethoxy-6'-methylbenzoyl)nonanoate (formula II-1wherein R=H₃ CO, X=H, Y=OH, n=8, in the form of methyl ester) (0.12part) in acetic acid (17 volume parts) was shaken with 5%palladium-on-carbon in a current of hydrogen gas at 50°-60° C. Thecatalyst was removed by filtration and the acetic acid was distilled offunder reduced pressure. The residue was subjected to columnchromatography on silicic acid (6 parts) and elution was carried outwith chloroform. The procedure provided methyl10-(2'-hydroxy-3',4'-dimethoxy-6'-methylphenyl)decanoate (formula II-2wherein R=H₃ CO, X=H, Y=OH, n=8, in the form of methyl ester) (0.09part) as a colorless oil.

Infrared absorption spectrum ν_(max) ^(film) cm⁻¹ : 3450(OH),1740(COOCH₃).

Nuclear magnetic resonance spectrum (τ in deuterochloroform):8.90-8.13(CH₂, multiplet), 7.83-7.43(ring CH₃ CH₂ CO, multiplet),7.73(ring CH₃, singlet), 6.37 (COOCH₃, singlet), 6.20(OCH₃, singlet),6.15(OCH₃, singlet), 4.20(OH, singlet), 3.73(ring proton, singlet).

EXAMPLE 15

5-(2'-Hydroxy-3',4',6'-trimethylbenzoyl)pentanoic acid (formula II-1wherein R=H₃ C, X=H, Y=OH, n=4, in the free form) (0.048 part) wasdissolved in 0.5% NaOH (3.3 volume parts) and, while the solution wasstirred at 20° C., potassium nitrosodisulfonate (0.4 part) was added.The mixture was stirred for 10 minutes. Then, under cooling with ice,the reaction mixture was diluted with water (100 volume parts) andrendered acidic with dilute hydrochloric acid. It was then extractedwith diethyl ether and the extract was washed with water and dried. Thesolvent was distilled off under reduced pressure and the residue wasthen recrystallized from hexane-ethyl acetate (2:1). The procedureprovided 2,3,5-trimethyl-6-(5'-carboxyl-1'-oxopentyl)-1,4-benzoquinone(formula I-1 wherein R=H₃ C, n=4, in the free form) (0.042 part) asyellow needles melting at 96.5°-98.5° C.

EXAMPLE 16

5-(2'-Hydroxy-3',4'-dimethoxy-6'-methylbenzoyl)pentanoic acid (formulaII-1 wherein R=H₃ CO, X=H, Y=OH, n=4, in the free form) (5.7 parts) wasoxidized by a procedure similar to that described in Example 15.Recrystallization of the oxidation product from hexane-diethyl etherprovided2,3-dimethoxy-5-methyl-6-(5'-carboxy-1'-oxopentyl)-1,4-benzoquinone(formula I-1 wherein R=H₃ CO, n=4, in the free form) (3.2 parts) asorange-red crystals melting at 48°-54° C.

Infrared absorption spectrum ν_(max) ^(KBr) cm⁻¹ : 1710(COOH),1710(CO),1675, 1655, 1610(quinone).

Nuclear magnetic resonance spectrum (τ in deuterochloroform): 8.31(CH₂,multiplet), 8.07(CH₃, singlet), 7.63(CH₂ CO, multiplet), 7.35(COCH₂,multiplet), 6.01(OCH₃, singlet).

Elemental analysis, C₁₅ H₁₈ O₇ -- Calculated: C, 58.06; H, 5.85. Found:C, 57.89; H, 5.90.

EXAMPLE 17

A mixture of2,3-dimethoxy-5-methyl-6-(5'-carboxy-1'-oxopentyl)-1,4-benzoquinone(formula I-1 wherein R=H₃ CO, n=4, in the free form) (0.12 part),toluene (10 volume parts), concentrated hydrochloric acid (1 volumepart), water (1 volume part) and zinc amalgam prepared from 1 part zincwas refluxed for 20 hours. After cooling, the reaction mixture wasextracted with diethyl ether, washed with water and dried. The solventswere distilled off under reduced pressure to obtain2,3-dimethoxy-5-methyl-6-(5'-carboxypentyl)benzohydroquinone (formulaII-2 wherein R=H₃ CO, X=Y=OH, n=4, in the free form)

Infrared absorption spectrum ν_(max) ^(film) cm⁻¹ : 3500(OH),1715(COOH).

Nuclear magnetic resonance spectrum (τ in deuterochloroform):8.75-8.20(CH₂, multiplet), 7.87(CH₃, singlet), 7.75-7.27(ring CH₂, CH₂COO, multiplet), 6.13(OCH₃, singlet).

EXAMPLE 18

In the presence of 5% palladium-on-carbon and in a current of hydrogengas, a solution of2,3,5-trimethyl-6-(5'-carboxy-1'-oxopentyl)-1,4-benzoquinone (formulaI-1 wherein R=H₃ C, n=4, in the free form) (1 part) in acetic acid (200volume parts) was stirred at 65°-70° C. for 4 hours. The catalyst wasfiltered off and the filtrate was concentrated under reduced pressure.The procedure provided2,3,5-trimethyl-6-(5'-carboxypentyl)benzohydroquinone (formula II-2wherein R=H₃ C, X=Y=OH, n=4, in the free form) (0.9 part) melting at145°-153° C.

EXAMPLE 19

2,3-Dimethoxy-5-methyl-6-(5'-carboxy-1'-oxopentyl)-1,4-benzoquinone(formula I-1 wherein R=H₃ CO, n=4, in the free form) (0.26 part) wasdissolved in a mixture of diethyl ether (20 volume parts) and ethylacetate (20 volume parts) and the solution was shaken with a solution ofsodium hydrosulfite (3 parts) in water (50 volume parts). The organiclayer was taken, washed with water and dried. The solvents were thenremoved by distillation under reduced pressure to obtain2,3-dimethoxy-5-methyl-6-(5'-carbonyl-1'-oxopentyl)benzohydroquinone(formula II-1 wherein R=H₃ CO, X=Y=OH, n=4, in the free form) (0.25part) as pale-yellow crystals melting at 110°-115° C.

EXAMPLE 20

2,3,5-Trimethyl-6-(5'-carboxy-1'-oxopentyl)-1,4-benzoquinone (formulaI-1 wherein R =H₃ C, n=4, in the free form) (1 part) was reduced by aprocedure similar to that described in Example 19. The procedureprovided 2,3,5-trimethyl-6-(5'-carboxy-1'-oxopentyl)benzohydroquinone(formula II-1 wherein R=H₃ C, X=Y=OH, n=4, in the free form) (0.9 part)as pale-yellow crystals melting at 106°-108° C.

EXAMPLE 21

A diethyl ether solution of2,3-dimethoxy-5-methyl-6-(5'-carboxypentyl)-1,4-benzoquinone (formulaI-2 wherein R=H₃ CO, n=4, in the free form) (0.84 part) was shaken witha solution of sodium hyrosulfite (10 parts) in water (100 volume parts).The ethereal layer was taken and treated in the conventional manner toobtain 2,3-dimethoxy-5-methyl-6-(5'-carboxypentyl)benzohydroquinone(formula II-2 wherein R=H₃ CO, X=Y=OH, n=4, in the free form) (0.69part) as a colorless oil.

EXAMPLE 22

2,3,5-Trimethyl-6-(5'-carboxypentyl)-1,4-benzoquinone (formula I-2wherein R=H₃ C, n=4, in the free form) was reduced by a proceduresimilar to that described in Example 21 to obtain2,3,5-trimethyl-6-(5'-carboxypentyl)hydroquinone (formula II-2 whereinR=H₃ C, X=Y=OH, n=4, in the free form) as colorless crystals melting at145°-153° C.

EXAMPLE 23

6-(2'-Hydroxy-3',4'-dimethoxy-6'-methylphenyl)hexanoic acid (formulaII-2 wherein R=H₃ CO, X=H, Y=OH, n=4, in the free form) was dissolved ina 5% solution of sodium hydroxide, followed by the addition of anaqueous solution of potassium persulfate. The mixture was stirred atroom temperature for 24 hours. The reaction mixture was rendered acidicwith hydrochloric acid and extracted with diethyl ether. The etherealextract was then treated in the conventional manner to obtain2,3-dimethoxy-5-methyl-6-(5'-carboxypentyl)benzohydroquinone (formulaII-2 wherein R=H₃ CO, X=Y=OH, n=4, in the free form) as a colorless oil.

EXAMPLE 24

6-(2'-Hydroxy-3',4',6'-trimethylphenyl)hexanoic acid (formula II-2wherein R=H₃ C, X=H, Y=OH, n=4, in the free form) was subjected to aprocedure similar to that described in Example 23. The procedureprovided 2,3,5-trimethyl-6-(5'-carboxypentyl)benzohydroquinone (formulaII-2 wherein R=H₃ C, X=Y=OH, n=4, in the free form) as colorlesscrystals melting at 145°-153° C.

EXAMPLE 25

Potassium nitrosodisulfonate (0.9 part) was added to a solution of6-(2'-hydroxy-3',4',6'-trimethylphenyl)hexanoic acid (formula II-2wherein R=H₃ C, X=H, Y=OH, n=4, in the free form) (0.111 part) in 1%sodium hydroxide (5 volume parts) and water (3 volume parts) and themixture was stirred at room temperature for 30 minutes. Then, thereaction mixture was cooled to 0° C. and, following the addition of coldwater (50 volume parts), it was rendered acidic with dilute hydrochloricacid, whereupon a yellow precipitate was obtained. Recrystallization ofthis precipitate from hexane-ethyl acetate (10:1) provided2,3,5-trimethyl-6-(5'-carboxypentyl)-1,4-benzoquinone (formula I-2wherein R=H₃ C, n=4, in the free form) (0.11 part) as yellow needlesmelting at 81°-82° C.

Infrared absorption spectrum ν_(max) ^(KBr) cm⁻¹ : 1705(COOH),1640(quinone).

Nuclear magnetic resonance spectrum (τ in deuterochloroform):8.8-8.1(CH₂, multiplet), 8.00(ring CH₃, singlet), 7.9-7.3(CH₂,multiplet).

Elemental analysis, C₁₅ H₂₀ O₄ -- Calculated: = C, 68.16; H, 7.63.Found: = C, 68.19; H, 7.61.

EXAMPLE 26

7-(2'-Hydroxy-3',4',6'-trimethylphenyl)heptanoic acid (formula II-2wherein R=H₃ C, X=H, Y=OH, n=5, in the free form) (1.02 part) wasoxidized by a procedure similar to that described in Example 25. Theprocedure provided2,3,5-trimethyl-6-(6'-carboxyhexyl)-1,4-benzoquinone(formula I-2 whereinR=H₃ C, n=5 in the free form) (0.82 part) as yellow needles melting at71°-72° C.

Infrared absorption spectrum ν_(max) ^(KBr) cm⁻¹ : 1710(COOH),1640(quinone).

Nuclear magnetic resonance spectrum (τ in deuterochloroform):8.9-8.1(CH₂, multiplet), 7.98(ring CH₃, singlet), 7.9-7.3(CH₂,multiplet).

Elemental analysis, C₁₆ H₂₂ O₄ -- Calculated: C, 69.04; H, 7.97. Found:C, 69.08; H, 8.04.

EXAMPLE 27

10-(2'-Hydroxy-3',4',6'-trimethylphenyl)decanoic acid (formula II-2wherein R=H₃ C, X=H, Y=OH, n=8, in the free form) (4 parts) was oxidizedby a procedure similar to that described in Example 25. The procedureprovided 2,3,5-trimethyl-6-(9'-carboxynonyl)-1,4-benzoquinone (formulaI-2 wherein R=H₃ C, n=8, in the free form) (1.47 part) as a yellow oil.

Infrared absorption spectrum ν_(max) ^(film) cm⁻¹ : 1705(COOH),1640(quinone).

Nuclear magnetic resonance spectrum(τ in deuterochloroform):8.9-8.1(CH₂, multiplet), 8.0(ring CH₃, singlet), 8.0-7.3(CH₂, multiplet)

Elemental analysis, C₁₉ H₂₈ O₄ -- Calculated: C, 71.22; H, 8.81. Found:C, 71.19; H, 8.80.

EXAMPLE 28

A solution of potassium nitrosodisulfonate (0.8 part) in water (10volume parts) was added to a solution of10-(2'-hydroxy-3',4'-dimethoxy-6'-methylphenyl)decanoic acid (formulaII-2 wherein R=H₃ CO, X=H, Y=OH, n=8, in the free form) (0.097 part) ina mixture of 1% sodium hydroxide (0.67 volume part) and acetone (2volume parts) and the mixture was stirred at room temperature for 2hours. The reaction mixture was rendered acidic with dilute hydrochloricacid and extracted with diethyl ether. The extract was washed with waterand dried, followed by evaporation to dryness. The procedure provided2,3-dimethoxy-5-methyl-6-(9'-carboxynonyl)-1,4-benzoquinone (formula I-2wherein R=H₃ CO, n=8, in the free form) (0.099 part) as orange-coloredneedles melting at 59°-60.5° C.

Nuclear magnetic resonance spectrum (τ in deuterochloroform): 8.82-8.25(CH₂, multiplet), 8.00(ring CH₃, singlet), 7.65(ring CH₂, CH₂ CO,triplet), 6.03(OCH₃, singlet), 0.22(COOH, broad).

Elemental analysis, C₁₉ H₂₈ O₆ -- Calculated: C, 64.75; H, 8.01. Found:C, 64.69; H, 8.11.

EXAMPLE 29

6-(2'-Hydroxy-3',4'-dimethoxy-6'-methylphenyl)hexanoic acid (formulaII-2 wherein R=H₃ CO, X=H, Y=OH, n=4 in the free form) (8.4 parts) wasoxidized by a procedure similar to that described in Example 28. Theprocedure provided2,3-dimethoxy-5-methyl-6-(5'-carboxypentyl)-1,4-benzoquinone (formulaI-2 wherein R=H₃ CO, n=4, in the free form) (7.6 parts) asorange-colored granules melting at 82°-86° C.

Nuclear magnetic resonance spectrum (τ in deuterochloroform):8.73-8.20(CH₂, multiplet), 7.97(ring CH₃, singlet), 7.60(ring CH₂, CH₂CO, triplet), 6.00(OCH₃, singlet), -0.55(COOH, broad)

Elemental analysis, C₁₅ H₂₀ O₆₋₋ Calculated: C, 60.80; H, 6.80. Found:C, 60.60; H, 6.81.

EXAMPLE 30

4-(2'-Hydroxy-3',4'-dimethoxy-6'-methylphenyl)butyric acid (formula II-2wherein R=H₃ CO, X=H, Y=OH, n=2, in the free form) (2.54 parts) wasoxidized by a procedure similar to that described in Example 28. Theprocedure provided2,3-dimethoxy-5-methyl-6-(3'-carboxypropyl)-1,4-benzoquinone (formulaI-2 wherein R=H₃ CO, n=2, in the free form) (2.2 parts) asorange-colored needles melting at 74°-75° C.

Elemental analysis, C₁₃ H₁₆ O₆ -- Calculated: C, 58.20; H, 6.01. Found:C, 58.03; H, 5.77.

EXAMPLE 31

To a well stirred solution of methyl10-(2'-hydroxy-3'-4'-dimethoxy-6'-methylphenyl)-decanoate (formula II-2wherein R=H₃ CO, X=H, Y=OH, n=8 in the form of methyl ester) (3.3 parts)in acetone (50 volume parts) were added potassium nitrosodisulfonate (10parts) and potassium biphosphate (10 parts). The procedure provided2,3-dimethoxy-5-methyl-6-(9'-methoxycarbonylnonyl)-1,4-benzoquinone(formula I-2 wherein R=H₃ CO, n=8, in the form of methyl ester) (1.5part) as orange-colored needles melting at 37°-37.5° C.

Elemetal analysis, C₂₀ H₃₀ O₆ -- Calculated: C, 65.55; H, 8.25. Found:C, 65.44; H, 8.36.

EXAMPLE 32

To 2,3-dimethoxy-5-methyl-6-(5'-carboxypentyl)benzohydroquinone (formulaII-2 wherein R=H₃ CO, X=Y=OH, n=4 in the free form) (0.08 part) wasadded a 10% solution of ferric chloride (150 volume parts), and themixture was shaken. It was then extracted with diethyl ether and theextract was washed with water and dried. The solvent was then distilledoff under reduced pressure. The residue was subjected to columnchromatography on silicic acid (10 parts) and the fraction eluted withchloroform-ethanol (49:1) was recrystallized from diethyl ether-hexane.The procedure provided2,3-dimethyoxy-5-methyl-6-(5'-carboxypentyl)-1,4-benzoquinone (formulaI-2 wherein R=H₃ CO, n=4, in the free form) (0.067 part) asorange-colored crystals melting at 83°-85° C.

EXAMPLE 33

A solution of 2,3,5-trimethyl-6-(5'-carboxypentyl)benzoquinone (formulaII-2 wherein R=H₃ C, X=Y=OH, n=4, in the free form) (0.9 part) indiethyl ether was shaken with a 10% solution of ferric chloride. Thereaction product was separated and purified by procedures similar tothose described in Example 32 to obtain2,3,5-trimethyl-6-(5'-carboxypentyl)-1,4-benzoquinone (formula I-2wherein R=H₃ C, n=4, in the free form) (0.6 part) as yellow needlesmelting at 81°-82° C.

EXAMPLE 34

The acid chloride (1.01 part) synthesized from2,3,5-trimethyl-6-(5'-carboxypentyl)-1,4-benzoquinone (formula I-2wherein R=H₃ C, n=4, in the free form) (1 part) and oxalyl chloride (5volume parts) was dissolved in anhydrous benzene (10 volume parts) andthe solution was added dropwise to a solution of salicylaldehyde (0.6part) in pyridine (10 volume parts) at 25° C. After stirring for 2.5hours, the reaction mixture was diluted with cold water (300 volumeparts) and rendered acidic with dilute hydrochloric acid. It was thenextracted twice with diethyl ether (300 volume parts). The extracts werepooled, washed with water and dried. The solvent was then distilled offunder reduced pressure and the residue was subjected to columnchromatography on silica gel. Elution with chloroform provided a yellowoil of 2,3,5-trimethyl-6-[5'-(o-formylphenyloxycarbonyl)pentyl]-1,4-benzoquinone (formula I-2 wherein R=H₃ C, n=4, in the formof o-formylphenolate) (1.3 part). To a cooled, stirred solution of thisproduct (1.1 part) in acetone (25 volume parts) was added standard Jonesreagent (2 volume parts). The solution was stirred for 100 minutes,after which it was diluted with cold water (500 volume parts), followedby extraction with ethyl acetate (500 volume parts). The extract waswashed with water and dried. The solvent was then distilled off underreduced pressure and the residue was purified by column chromatographyon silica gel (50 parts). The procedure provided a yellow oil of2,3,5-trimethyl-6-[5'-(o-carboxyphenyloxycarbonyl)pentyl]-1,4-benzoquinone (formula I-2 wherein R=H₃ C, n=4, in the formof o-carboxyphenolate) (1.1 part).

EXAMPLE 35

A mixture of 2,3,5-trimethyl-6-(5'-carboxypentyl)-1,4-benzoquinone(formula I-2 wherein R=H₃ C, n=4, in the free form) (0.2 part), benzylchloride (0.4 part), silver oxide (0.283 part) and benzene was refluxedfor 19 hours. The insolubles were filtered off and the filtrate wasconcentrate under reduced pressure. The concentrate was then subjectedto column chromatography on silica gel to recover a yellow oil of2,3,5-trimethyl-6-(5'-benzyloxycarbonylpentyl)-1,4-benzoquinone (formulaI-2 wherein R=H₃ C, n=4, in the form of benzylester) (0.189 part).

EXAMPLE 36

2,3-Dimethoxy-5-methyl-6-(9'-carboxynonyl)-1,4-benzoquinone (formula I-2wherein R=H₃ CO, n=8, in the free form) (4 parts) was esterified withmethanol (500 volume parts) saturated with hydrogen chloride gas in amanner similar to that described in Example 13. The procedure provided2,3-dimethoxy-5-methyl-6-(9'-methoxycarbonylnonyl)-1,4-benzoquinone(formula I-2 wherein R=H₃ CO, n=8, in the form of methyl ester) (4.2parts) as orange-colored needles melting at 37°-37.5° C.

EXAMPLE 37

To a methanolic solution of2,3-dimethoxy-5-methyl-6-(9'-methoxycarbonylnonyl)-1,4-benzoquinone(formula I-2 wherein R=H₃ CO, n=8, in the form of methylester) (0.17part) and pyrogallol (1.6 part) was added a 10% methanolic solution ofpotassium hydroxide (40 volume parts) and the mixture was refluxed for 2hours. The reaction mixture was rendered acidic with hydrochloric acidand extracted with diethyl ether. The ethereal extract was shakentogether with a 10% aqueous solution of ferric chloride and the ethereallayer was taken, washed with water and dried. The diethyl ether wasdistilled off under reduced pressure to recover2,3-dimethoxy-5-methyl-6-(9'-carboxynonyl)-1,4-benzoquinone (formula I-2wherein R=H₃ CO, n=8, in the free form) (0.08 part).

EXAMPLE 38

9-(2',3',4'-Trimethoxy-6'-methylbenzoyl)nonanoic acid (formula II-1wherein R=Y=H₃ CO, X=H, n=8, in the free form) (0.09 part) was reducedwith zinc amalgam (0.2 part) by a procedure similar to that described inExample 10 and oxidized with 30% hydrogen peroxide (10 volume parts) inacetic acid. Following the addition of water, the reaction mixture wasextracted with diethyl ether (500 volume parts) and the extract waswashed with water and dried. The ether was then removed by distillation.The procedure provided2,3-dimethoxy-5-methyl-6-(9'-carboxynonyl)-1,4-benzoquinone (formula I-2wherein R=H₃ CO, n=8, in the free form).

EXAMPLE 39

To a solution of 2,3-dimethoxy-5-methyl-1,4-benzoquinone (formula Vwherein R=H₃ CO) (3.64 parts) in acetic acid (20 volume parts), therewas added disebacoyl peroxide diethyl ester (9.2 parts) in smallportions at 85° C. The mixture was further stirred at 85° C. for 2hours. After cooling, water was added to the reaction mixture, followedby extraction with diethyl ether. The ethereal extract was washed with asaturated aqueous solution of sodium hydrogen carbonate and dried overanhydrous sodium sulfate. The diethyl ether was then distilled off underreduced pressure. The resulting orange-colored oily residue wascolumn-chromatographed on silica gel, and elution was carried out withhexane-diethyl ether. The procedure provided2,3-dimethoxy-5-methyl-6-(8'-ethoxycarbonyloctyl)-1,4-benzoquinone(formula I-2 wherein R=H₃ CO, n=7, in the form of ethylester) (1.79part) as an orange-colored oil.

Infrared absorption spectrum ν_(max) ^(film) cm⁻¹ : 1730(ester), 1660,1650, 1615 (quinone).

Nuclear magnetic resonance spectrum (τ in carbon tetrachloride): 8.76(CH₃, triplet), 8.66(CH₂, broad), 8.04 (ring CH₃, singlet), 7.77(ringCH₂, triplet), 7.80-7.37 (CH₂ COO, broad), 6.05(CH₃ O, singlet).5.95(COOCH₂, quartet)

Elemental analysis, C₂₀ H₃₀ O₆ -- Calculated: C, 65.55; H, 8.25. Found:C, 65.02; H, 8.07.

To a solution of2,3-dimethoxy-5-methyl-6-(8'-ethoxycarbonyloctyl)-1,4-benzoquinone(formula I-2 wherein R=H₃ CO, n=7, in the form of ethylester) (0.8 part)in diethyl ether (10 volume parts), followed by the addition of a 30%solution (20 volume parts) of potassium hydroxide containing sodiumhydrosulfite. The mixture was refluxed for 1 hour. After cooling, thereaction mixture was rendered acidic with hydrochloric acid andextracted with diethyl ether. The ethereal extract was washed with waterand shaken together with a solution of ferric chloride. The ethereallayer was washed with water and dried over anhydrous sodium sulfate. Thediethyl ether was distilled off under reduced pressure and the resultingresidue was crystallized from diethyl ether-hexane. The procedureprovided 2,3-dimethoxy-5-methyl-6-(8'-carboxyoctyl)-1,4-benzoquinone(formula I-2 wherein R=H₃ CO, n=7, in the free form) (0.53 part) asorange-colored needles melting at 39°-40.5° C.

Elemental analysis, C₁₈ H₂₆ O₆ -- Calculated: C, 63.88; H, 7.74. Found:C, 63.60; H, 7.88.

EXAMPLE 40

2,3,5-Trimethyl-1,4-benzoquinone (formula V wherein R=H₃ C) (1 part) wasreacted with disuccinoyl peroxide dimethyl ester (1.4 part) by aprocedure similar to that described in Example 39. The procedureprovided 2,3,5-trimethyl-6-(2'-methoxycarbonylethyl)-1,4-benzoquinone(formula I-2 wherein R=H₃ C, n=1, in the form of methyl ester) (0.55part) as a yellow oil.

Infrared absorption spectrum ν_(max) ^(film) cm⁻¹ : 1740(ester),1640(quinone).

Nuclear magnetic resonance spectrum (τ in deuterochloroform): 8.02 (ringCH₃, singlet), 7,95 (ring CH₃, singlet), 7.53 (CH₂ COO, triplet), 7.18(ring CH₂, triplet), 6.50 (COOCH₃, singlet).

The above product (0.082 part) was hydrolyzed in the same manner asExample 39 and the resulting yellow oil was crystallized from diethylether-hexane. The procedure provided2,3,5-trimethyl-6-(2'-carboxyethyl)-1,4-benzoquinone (formula I-2wherein R=H₃ C, n=1, in the free form) (0.058 part) as pale yellowishneedles melting at 112°-114° C.

Elemental analysis, C₁₂ H₁₄ O₄ -- Calculated: C, 64.85; H, 6.35. Found:C, 64.84; H, 6.32.

EXAMPLE 41

To a solution of 2,3-dimethoxy-5-methyl-1,4-benzoquinone (formula Vwherein R=H₃ CO) (0.91 part) in acetic acid (10 volume parts) was addeddisuccinoyl peroxide (2 parts) at 90° C. and the mixture was heated atthe same temperature for 4 hours.

Thereafter, the reaction mixture was treated in the same manner asExample 39 to obtain2,3-dimethoxy-5-methyl-6-(2'-carboxyethyl)-1,4-benzoquinone (formula I-2wherein R=H₃ CO, n=1, in the free form) (0.4 part) as orange-redcrystals melting at 122°-124° C.

Elemental analysis, C₁₂ H₁₄ O₆ -- Calculated: C, 56.69; H, 5.55. Found:C, 56.91; H, 5.24.

EXAMPLE 42

A solution of ethyl 5-(2'-hydroxy-3',4',6'-trimethylbenzoyl)pentanoate(formula II-1 wherein R=H₃ C, X=H, Y=OH, n=4, in the form of ethylester) (0.4 part) in tetrahydrofuran (100 volume parts) was reduced withlithium aluminum hydride (0.5 part) under warming for 1 hour. Thereaction mixture was quenched with ethyl acetate followed by theaddition of saturated aqueous sodium sulfate (5 volume parts) solution.After removal of the resulting inorganic salt by filtration, thefiltrate was condensed in vacuo to dryness. The residue was crystallizedfrom diethyl ether to give1-(2'-hydroxy-3',4',6'-trimethylphenyl)-1,6-hexanediol (formula III-3wherein R=H₃ C, X=H, Y=OH, n=4, in the free form) (0.32 part) ascolorless needles melting at 135°-136° C.

Elemental analysis C₁₅ H₂₄ O₃ -- Calculated: C, 71.39; H, 9.59. Found:C, 71.38; H, 9.54.

EXAMPLE 43

To a well stirred suspension of lithium aluminum hydride (2 parts) indry tetrahydrofuran (50 volume parts) was added a solution of5-(2'-hydroxy-3',4',6'-trimethylbenzoyl)pentanoic acid (formula II-1wherein R=H₃ C, X=H, Y=OH, n=4, in the free form) in dry tetrahydrofuran(10 volume parts) at room temperature. After being stirred under refluxfor 2 hours, the mixture was cooled to 0° C., acidified with cold dilutehydrochloric acid, and extracted with ethyl acetate. The ethyl acetateextract was washed with water, dried over anhydrous sodium sulfate, andconcentrated in vacuo. The resulting residue was subjected to columnchromatography on silica gel and eluted with carbontetrachloride-acetone (5:1). From the 1st fraction,6-hydroxy-6-(2'-hydroxy-3',4',6'-trimethylphenyl)hexanoic acid (formulaII-3 wherein R=H₃ C, X=H, Y=OH, n=4, in the free form) (0.45 part) wasobtained as colorless needles melting at 165°-166° C.

Elemental analysis, C₁₅ H₂₂ O₄ -- Calculated: C, 67.64; H, 8.33. Found:C, 67.63; H, 8.13.

From the 2nd fraction,1-(2'-hydroxy-3',4',6'-trimethylphenyl)-1,6-hexanediol (formula III-3wherein R=H₃ C, X=H, Y=OH, n=4, in the free form) (2.5 parts) wasobtained. This compound was identified with the product obtained inExample 42.

EXAMPLE 44

To a solution of6-hydroxy-6-(2'-hydroxy-3',4',6'-trimethylphenyl)hexanoic acid (formulaIII-3 wherein R=H₃ C, X=H, Y=OH, n=4, in the free form) (0.158 part) in5% sodium hydroxide solution (2 volume parts) and water (7 volume parts)was added Fremy's salt (1 part) at room temperature with stirring. Afterbeing stirred for 1 hour, the mixture was cooled to 0° C., acidifiedwith cold dilute hydrochloric acid, and extracted with ethyl acetate.The extract was washed with water, dried over anhydrous sodium sulfate,and concentrated in vacuo. The resulting residue was subjected to columnchromatography on silica gel and eluted with chloroform-methanol (20:1).The product was recrystallized from ethylacetate-hexane (1:2) to give2,3,5-trimethyl-6-(5'-carboxy-1'-hydroxypentyl)-1,4-benzoquinone(formula I-3 wherein R=H₃ C, n=4, in the free form) (0.128 part) asbrown needles melting at 130°-131.5° C.

Elemental analysis, C₁₅ H₂₀ O₅ -- Calculated: C, 64.27; H, 10.24. Found:C, 64.03; H, 7.22.

EXAMPLE 45

A solution of 1-(2'-hydroxy-3',4',6'-trimethylphenyl)-1,6-hexanediol(formula III-3 wherein R=H₃ C, X=H, Y=OH, n=4, in the free form) (5.43parts) in acetic acid (150 volume parts) was stirred with 5% palladiumon carbon (4.79 parts) under a stream of hydrogen gas at roomtemperature until the uptake of hydrogen ceased. The catalyst wasfiltered off and the filtrate was concentrated in vacuo. The resultingresidue was subjected to column chromatography on silica gel and elutedwith chloroform-methanol (100:1). From the 1st fraction,6-(2'-hydroxy-3',4',6'-trimethylphenyl)hexanol (formula III-2, whereinR=H₃ C, X=H, Y=OH, n=4, in the free form) (0.872 part) was obtained ascolorless needles melting at 81°-82° C.

Elemental analysis, C₁₅ H₂₄ O₂ -- Calculated: C, 76.22; H, 10.24. Found:C, 76.08; H, 10.33.

From the 2nd fraction, the starting material (2.31 parts) was recovered.

EXAMPLE 46

To a solution of 6-(2'-hydroxy-3',4',6'-trimethylphenyl)hexanol (formulaIII-2, wherein R=H₃ C, X=H, Y=OH, n=4, in the free form) (0.02 part) in1% sodium hydroxide solution (25 parts) was added Fremy's salt (0.2part) at room temperature with stirring. After being stirred for 1 hour,the mixture was cooled to 0° C., acidified with dilute hydrochloricacid, and extracted with ethyl acetate. The extract was washed withwater, dried over anhydrous sodium sulfate, and concentrated in vacuo togive 2,3,5-trimethyl-6-(6'-hydroxyhexyl)-1,4-benzoquinone (formula IV-2wherein R=H₃ C, n=4, in the free form) (0.02 part) as yellow needlesmelting at 43°-45° C.

EXAMPLE 47

To a solution of 1-(2'-hydroxy-3',4',6'-trimethylphenyl)-1,6-hexanediol(formula III-3 wherein R=H₃ C, X=H, Y=OH, n=4 in the free form) (0.32part) in dimethyl formamide (20 volume parts) was added all at once amixture of Fremy's salt (0.5 part) and potasium biphosphate(0.5 part) inwater (50 volume parts). The mixture was stirred for 3 hours at roomtemperature. The reaction product was taken up with diethyl ether. Thediethyl ether layer was washed with water and dried over anhydroussodium sulfate. The residue upon removal of the solvent was subjected tochromatography on silica gel and eluted with ethyl acetate-diethyl ether(4:1) to give 2,3,5-trimethyl-6-(1',6'-dihydroxyhexyl)-1,4-benzoquinone(formula IV-3 wherein R=H₃ C, n=4, in the free form) (0.26 part) as ayellow oil.

Infrared absorption spectrum ν_(max) ^(film) cm⁻¹ : 3400(OH), 1640(quinone).

Nuclear magnetic resonance spectrum (τ in deuterochloroform): 8.55 (CH₂,broad), 8.00 (ring CH₃ singlet), 6.40(ring CH₂, triplet), 5.35(CH-O,broad).

Mass spectrum (m/e) C₁₅ H₂₂ O₄ :M⁺ (266).

EXAMPLE 48

To a solution of2,3,5-trimethyl-6-(1',6'-dihydroxyhexyl)-1,4-benzoquinone (formula IV-3wherein R=H₃ C, n=4, in the free form) (1.17 part) in anhydrous pyridine(15 volume parts) was added a solution of acetic anhydride (0.473 part)in pyridine (5 volume parts) dropwise under stirring at 5° C. Themixture was allowed to stand over night at room temperature. Afterremoval of the solvents in vacuo, the residue was separated into twofractions by chromatography on silica gel and eluted with methylenechloride-diethyl ether (9:1). The 1st fraction afforded2,3,5-trimethyl-6-(1',6'-diacetoxyhexyl)-1,4-benzoquinone (formula IV-3wherein R=H₃ C, n=4, in the form of diacetate at --CH₂ OH and ##STR14##(0.265 part) as a yellow oil.

Infrared absorption spectrum ν_(max) ^(film) cm⁻¹ : 1740, 1370, 1250,1040(OCOCH₃), 1640(quinone).

Nuclear magnetic resonance spectrum (τ in deuterochloroform): 8.50(CH₂,broad), 7.99, 7.98, 7.95, 6.85 (ring CH₃, OCOCH₃), 5.96(CH₂ -O,triplet), 4.05(CH-O, triplet).

The 2nd fraction from the above mentioned chromtography afforded2,3,5-trimethyl-6-(6'-acetoxy-1'-hydroxyhexyl)-1,4-benzoquinone (formulaIV-3 wherein R=H₃ C, n=4, in the form of acetate at --CH₂ OH) (0.767part) as a yellow oil.

Infrared absorption spectrum ν_(max) ^(film) cm⁻¹ : 3500(OH), 1740,1250, 1040(OCOCH₃), 1640(quinone)

Nuclear magnetic resonance spectrum (τ in deuterochloroform): 8.50(CH₂,broad), 7.99, 7.98, 7.97 (ring CH₃, OCOCH₃), 5.96(CH₂ -O, triplet), 4.05(CH-O, triplet).

Mass spectrum (m/e) C₁₇ H₂₄ O₅ :M⁺ (308).

EXAMPLE 49

A solution of2,3,5-trimethyl-6-(6'-acetoxy-1'-hydroxyhexyl)-1,4-benzoquinone (formulaIV-3 wherein R=H₃ C, n=4, in the form of acetate at --CH₂ OH) (0.74part) in acetone (20 volume parts) was oxidized at 5° C. for 5 minuteswith Jones reagent (0.6 volume part) prepared by dissolving chromictrioxide (26.72 parts) in concentrated sulfuric acid (23 volume parts)diluted with water to a volume of 100 volume parts. The resultingprecipitate was decomposed with water, and the product was taken up withdiethyl ether. The organic layer was washed with water and dried overanhydrous sodium sulfate. The residue upon removal of the solvent wassubjected to column chromatography on silica gel and eluted withmethylene chloride and the resulting product was crystallized frompetroleum ether to give2,3,5-trimethyl-6-(6'-acetoxy-1'-oxohexyl)-1,4-benzoquinone (formulaIV-1 wherein R=H₃ C, n=4, in the form of acetate) (0.638 part) as yellowcrystals melting at 57° C.

Mass spectrum (m/e) C₁₇ H₂₂ O₅ :M⁺ (306).

EXAMPLE 50

To a stirred mixture of2,3,5-trimethyl-6-(6'-acetoxy-1'-oxohexyl)-1,4-benzoquinone (formulaIV-1 wherein R=H₃ C, n=4, in the form of acetate) (0.5 part), sodiumhydrosulfite (1 part) and 30% aqueous methanol (20 volume parts) wasadded dropwise 2N aqueous sodium hydroxide (1.6 volume part) at 5° C.The mixture was allowed to stand for 3 hours at the same temperature.After removal of the methanol and acidification with phosphoric acid,the product was extracted with ethyl acetate. The organic layer waswashed with water, dried over anhydrous sodium sulfate, and evaporatedin vacuo. The residue was subjected to chromatography on silica gel andeluted with ethyl acetate to give2,3,5-trimethyl-6-(6'-acetoxy-1'-oxohexyl)hydroquinone. (formula III-1wherein R=H₃ C, X=Y=OH, n=4, in the form of acetate) (0.075 part).Further elution with the same solvent gave2,3,5-trimethyl-6-(6'-hydroxy-1'-oxohexyl)-hydroquinone. (formula III-1wherein R=H₃ C, X=Y=OH, n=4, in the free form) (0.265 part).

Infrared absorption spectrum ν_(max) ^(film) cm⁻¹ : 3450(OH), 1690(quinone).

Nuclear magnetic resonance spectrum(τ in deuterochloroform): 8.40(CH₂,broad), 7.90(ring CH₃, singlet), 7.83(ring CH₃, singlet), 7.70(ring CH₃,singlet), 7.15(COCH₂, broad), 6.40(CH₂ -O, broad).

EXAMPLE 51

A solution of 2,3,5-trimethyl-6-(6'-hydroxy-1'-oxohexyl)-hydroquinone(formula III-1 wherein R=H₃ C, X=Y=OH, n=4, in the free form) (0.1 part)in diethyl ether (10 volume parts) was stirred with 3% aqueous ferricchloride solution at room temperature for 2 hours. The organic layer wasseparated and the aqueous layer was extracted with ethyl acetate. Thecombined organic layer and diethyl ether extract were washed with water,dried over anhydrous sodium sulfate, and evaporated in vacuo to dryness.The residue was subjected to chromatography on silica gel and elutedwith diethyl ether to give2,3,5-trimethyl-6-(6'-hydroxy-1'-oxohexyl)-1,4-benzoquinone (formulaIV-1 wherein R=H₃ C, n=4, in the free form) (0.088 part) as a yellowoil.

Infrared absorption spectrum ν_(max) ^(film) cm⁻¹ : 3450(OH), 1690(CO),1640(quinone).

Nuclear magnetic resonance spectrum(τ in deuterochloroform): 8.50(CH₂,broad), 8.06(ring CH₃, singlet), 7.97(ring CH₃, singlet), 7.40(COCH₂,triplet), 6.37(CH₂ -O, triplet).

Mass spectrum (m/e) C₁₅ H₂₀ O₄ :M⁺ (264).

EXAMPLE 52

A solution of2,3-dimethoxy-5-methyl-6-(3'-carboxypropyl)-1,4-benzoquinone (formulaI-2 wherein R=H₃ CO, n=2 in the free form (0.8 part) in ethanol (3volume parts) saturated with dry hydrogen chloride was stirred at roomtemperature for 1 hour. The residue upon removal of the solvent wassubjected to chromatography on silica gel and eluted with chloroform togive 2,3-dimethoxy-5-methyl-6-(3'-ethoxycarbonylpropyl)-1,4-benzoquinone(formula I-2 wherein R=H₃ CO, n=2, in the form of ethyl ester) (0.88part) as an orange oil.

Infrared absorption spectrum ν_(max) ^(film) cm⁻¹ : 1730(COOC₂ H₅),1660, 1640, 1610(quinone).

Nuclear magnetic resonance spectrum(τ in deuterochloroform): 8.74(CH₃,triplet), 8.56-8.00 (CH₂, multiplet), 7.96(ring CH₃, singlet), 7.65(CH₂COO, triplet), 7.46(ring CH₂, triplet), 5.99(OCH₃, Singlet),5.86(COOCH₂, quartet).

Elemental analysis, C₁₅ H₂₀ O₆ -- Calculated: C, 60.80; H, 6.80. Found:C, 61.26; H, 7.12.

EXAMPLE 53

To a well stirred solution of lithium aluminum hydride (0.5 part) indiethyl ether (5 volume parts) was added a solution of2,3-dimethoxy-5-methyl-6-(3'-ethoxycarbonylpropyl)-1,4-benzoquinone(formula I-2 wherein R=H₃ CO, n=2, in the form of ethyl ester) (0.78part) in diethyl ether (10 volume parts) under cooling in ice-bath.After stirring at room temperature for 1 hour, the mixture was acidifiedwith dilute hydrochloric acid. The diethyl ether layer was separated andthe aqueous layer was extracted with diethyl ether. The combined diethylether and extract were washed with water, dried over anhydrous sodiumsulfate. The diethyl ether was removed in vacuo to give2,3-dimethoxy-5-methyl-6-(4'-hydroxybutyl)-hydroquinone (formula III-2wherein R=H₃ CO, n=2, in the free form). A solution of the above productin diethyl ether was shaken with 16% aqueous ferric chloride (10 volumeparts). The diethyl ether layer was separated, washed with water anddried over anhydrous sodium sulfate. The residue upon removal of thesolvent was subjected to chromatography on silica gel and eluted withchloroform to give2,3-dimethoxy-5-methyl-6-(4'-hydroxybutyl)-1,4-benzoquinone (formulaIV-2 wherein R=H₃ CO, n=2, in the free form) (0.52 part) as an orangeoil.

Infrared absorption spectrum ν_(max) ^(film) cm⁻¹ : 3400(OH), 1660,1640, 1610(quinone).

Nuclear magnetic resonance spectrum (τ in deuterochloroform):8.62-8.24(CH₂, multiplet), 8.10(OH, singlet), 7.98(ring CH₃, singlet),7.50(ring CH₂, triplet), 6.32(CH₂ O, triplet), 6.00(OCH₃, singlet).

Elemental analysis, C₁₃ H₁₈ O₅ -- Calculated: C, 61.40; H, 7.14. Found:C, 61.47; H, 7.32.

EXAMPLE 54

2,3-Dimethoxy-5-methyl-6-(9'-methoxycarbonylnonyl)-1,4-benzoquinone(formula I-2 wherein R=H₃ CO, n=8, in the form of methyl ester) (1 part)was treated with lithium aluminum hydride in the same manner as Example53 to give 2,3-dimethoxy-5-methyl-6-(10'-hydroxydecyl)-hydroquinone(formula III-2 wherein R=H₃ CO, X=Y=OH, n=8, in the free form). Theproduct was treated with ferric chloride in the same manner as Example53 and then crystallized from ligroin. The procedure provided2,3-dimethoxy-5-methyl-6-(10'-hydroxydecyl)-1,4-benzoquinone (formulaIV-2 wherein R=H₃ CO, n=8, in the free form) (0.65 part) as orangeneedles melting at 46°-50° C.

Elemental analysis, C₁₉ H₃₀ O₅ -- Calculated: C, 67.43; H, 8.94. Found:C, 67.41; H, 8.94.

EXAMPLE 55

To a cooled, well stirred solution of2,3-dimethoxy-5-methyl-6-(10'-hydroxydecyl)-1,4-benzoquinone (formulaIV-2 wherein R=H₃ CO, n=8, in the free form) (0.3 part) in pyridine (1volume part) was added acetic anhydride (0.1 volume part). Afterstirring at room temperature for 1 hour, the mixture was diluted withwater, and the aqueous solution was extracted with diethyl ether. Theextract was washed successively with water, dilute hydrochloric acid,water, saturated aqueous sodium hydrogen carbonate and water, and driedover anhydrous sodium sulfate. The residue upon removal of the solventwas crystallized from aqueous ethanol to give2,3-dimethoxy-5-methyl-6-(10'-acetoxydecyl)-1,4-benzoquinone (formulaIV-2 wherein R=H₃ CO, n=8, in the form of acetate) (0.31 part) as orangeneedles melting at 38° C.

Elemental analysis, C₂₁ H₃₂ O₆ -- Calculated: C, 66.30; H, 8.48. Found:C, 66.12; H, 8.59.

EXAMPLE 56

A solution of2,3,5-trimethyl-6-(2'-ethoxycarbonylethyl)-1,4-benzoquinone (formula I-2wherein R=H₃ C, n=1, in the form of ethyl ester) (0.39 part) in diethylether (50 volume parts) was treated with lithium aluminum hydride in thesame manner as Example 53 to give2,3,5-trimethyl-6-(3'-hydroxypropyl)-hydroquinone (formula III-2 whereinR=H₃ C, X=Y=OH, n=1 in the free form). The product was treated withferric chloride in the same manner as Example 53 and then subjected tocolumn chromatography on silica gel and eluted with chloroform. Theprocedure provided 2,3,5-trimethyl-6-(3'-hydroxypropyl)-1,4-benzoquinone(formula IV-2 wherein R=H₃ C, n=1, in the free form) (0.25 part) as ayellow oil.

Infrared absorption spectrum ν_(max) ^(film) cm⁻¹ : 3400(OH),1640(quinone).

Nuclear magnetic resonance spectrum(τ deuterochloroform): 8.50-8.06(CH₂,multiplet), 7.96(ring CH₃ singlet), 7.94(ring CH₃, singlet), 7.84(OH,broad), 7.40(ring CH₂, triplet), 6.40(CH₂ O, triplet).

Mass spectrum (m/e) C₁₂ H₁₆ O₃ :M⁺ (208).

EXAMPLE 57

To a well stirred solution of2,3,5-trimethyl-6-(5'-carboxypentyl)-1,4-benzoquinone (formula I-2wherein R=H₃ C, n=4, in the free form) (0.21 part) in ethanol (10 volumeparts) was added 3 drops of concentrated sulfuric acid under cooling inice bath and kept standing for 12 hours. After addition of water, thereaction mixture was extracted with diethyl ether and the diethyletherlayer was washed with water and dried over anhydrous sodium sulfate. Theresidue upon removal of the solvent was subjected to chromatography onsilica gel and eluted with chloroform to give2,3,5-trimethyl-6-(5'-ethoxycarbonylpentyl)-1,4-benzoquinone (formulaI-2 wherein R=H₃ C, n=4, in the form of ethyl ester) (0.20 part) as anorange oil.

Infrared absorption spectrum σ_(max) ^(film) cm⁻¹ : 1640 (quinone).

Nuclear magnetic resonance spectrum (τ in deuterochloroform): 8.76(CH₃,triplet), 8.80-8.30(CH₂, multiplet), 8.0 (ring CH₃, singlet),8.00-7.30(ring CH₂, CH₂ COO, multiplet), 5.88(COOCH₂, quartet).

Elemental analysis, C₁₇ H₂₄ O₄ -- Calculated: C, 69.83; H, 8.27. Found:C, 69.85; H, 8.36.

EXAMPLE 58

A solution of2,3,5-trimethyl-6-(5'-ethoxycarbonylpentyl)-1,4-benzoquinone (formulaI-2 wherein R=H₃ C, n=4, in the form of ethylester) (0.1 part) indiethyl ether (10 volume parts) was treated with lithium aluminumhydride in the same manner as Example 53 to give2,3,5-trimethyl-6-(6'-hydroxyhexyl)-hydroquinone (formula III-2 whereinR=H₃ C, n=4, in the free form). The product was treated with ferricchloride in the same manner as Example 53 and then crystallized fromdiethyl ether. The procedure provided2,3,5-trimethyl-6-(6'-hydroxyhexyl)-1,4-benzoquinone (formula IV-2,wherein R=H₃ C, n=4 in the free form) as yellow needles melting at43°-45° C.

Elemental analysis C₁₅ H₂₂ O₃ -- Calculated: C, 71.97; H, 8.86. Found:C, 72.33; H, 8.58.

EXAMPLE 59

Some examples of practical recipes in which the compounds of thisinvention are utilized for the physiologic host defense control are asfollows:

A (Capsule)

(a)

    ______________________________________                                        (1) 2,3-dimethoxy-5-methyl-6-(3'-ethoxycarbonylpropyl)-                         1,4-benzoquinone    20 mg                                                   (2) Corn oil         150 mg                                                                        170 mg                                                                        per capsule                                              ______________________________________                                    

(1) is added to (2), and then warmed to about 40° C. to dissolve (1) in(2). The whole is filled into a gelatin capsule.

(b)

    ______________________________________                                        (1) 2,3,5-trimethyl-6-(6'-hydroxyhexyl)-                                        1,4-benzoquinone     20 mg                                                  (2) corn oil          150 mg                                                                        170 mg                                                                        per capsule                                             ______________________________________                                    

Capsule is prepared in a similar manner as A-(a).

B (Tablet)

    ______________________________________                                        (1) 2,3,5-trimethyl-6-(5'-carboxypentyl)-1,4-                                 benzoquinone            20 mg                                                 (2) lactose             35 mg                                                 (3) corn starch        150 mg                                                 (4) microcrystalline cellulose                                                                        30 mg                                                 (5) magnesium stearate  5 mg                                                                         240 mg                                                                        per tablet                                             ______________________________________                                    

(1),(2),(3), 2/3 quantity of (4) and half quantity of (5) are thoroughlymixed, and then the mixture is graulated. Remaining 1/3 quantity of (4)and half of (5) are added to the granules and compressed into tablets.Thus prepared tablets can further be coated with a suitable coatingagent, e.g. sugar.

C (Injection)

(a)

    ______________________________________                                        (1) 2,3-dimethoxy-5-methyl-6-(2'-carboxyethyl)-1,4                            benzoquinone           10 mg                                                  (2) sodium bicarbonate 3.3 mg                                                 (3) sodium chloride    0.018 mg                                               ______________________________________                                    

(1) is dissolved in 1.5 ml of aqueous solution containing (2), to which(3) is added, then water is supplemented to make the whole volume 2.0ml.

(b)

    ______________________________________                                        (1) 2,3-dimethoxy-5-methyl-6-(5'-carboxy-1'-oxopentyl)                        1,4-benzoquinone       10 mg                                                  (2) sodium bicarbonate 2.7 mg                                                 (3) sodium chloride    0.018 mg                                               ______________________________________                                    

An injection is prepared in a similar manner as C-(a).

(c)

    ______________________________________                                        (1) 2,3,5-trimethyl-6-(5'-carboxy-1'-hydroxy-                                 pentyl)-1,4-benzoquinone                                                                             10 mg                                                  (2) sodium bicarbonate 3 mg                                                   (3) sodium chloride    0.018 mg                                               ______________________________________                                    

An injection is prepared in a similar manner as C-(a).

What we claim is:
 1. A compound selected from the group consisting ofcompounds of the formula ##STR15## wherein R represents alkyl of 1-4carbon atoms or alkoxy of 1-4 carbon atoms, A represents --CH₂ --,--CO-- or ##STR16## and n represents an integer of from 1 to 8 when A is--CO-- or ##STR17## when both A is --CH₂ -- and R is alkoxy of 1-4carbon atoms and an integer of from 4 to 8 when both A is --CH₂ -- and Ris alkyl of 1-4 carbon atoms,alkyl esters of said compounds wherein thealkyl moiety of said alkyl esters has 1-4 carbon atoms, aryl esters ofsaid compounds wherein the aryl moiety of said aryl esters has 6-7carbon atoms, and aralkyl esters of said compounds wherein the aralkylmoiety of said aralkyl esters has 7-8 carbon atoms, said alkyl, aryl amdaralkyl moieties of said esters being unsubstituted or substituted by atleast one of sulfo, carboxyl, formyl, hydroxyl and amino.
 2. A compoundas claimed in claim 1, wherein A is --CH₂ --.
 3. A compound as claimedin claim 1, wherein A is --CO--.
 4. A compound as claimed in claim 1,wherein A is ##STR18##
 5. A compound as claimed in claim 1, wherein R isalkyl of 1-4 carbon atoms.
 6. A compound as claimed in claim 5, whereinn is 4 or
 5. 7. A compound as claimed in claim 5, wherein R is methyl.8. A compound as claimed in claim 1, wherein R is alkoxy of 1-4 carbonatoms.
 9. A compound as claimed in claim 8, wherein R is methoxy.
 10. Acompound as claimed in claim 1, wherein the compound is in the form ofan alkyl ester in which the alkyl moiety of said alkyl ester has 1-4carbon atoms, said alkyl moiety of said ester being unsubstituted orsubstituted by at least one of sulfo, carboxyl, formyl, hydroxyl andamino.
 11. A compound as claimed in claim 1, wherein the compound is inthe form of an aryl ester in which the aryl moiety of said aryl esterhas 6-7 carbon atoms, said aryl moiety of said ester being unsubstitutedor substituted by at least one of sulfo, carboxyl, formyl, hydroxyl andamino.
 12. A compound as claimed in claim 1, wherein the compound is inthe form of an aralkyl ester in which the aralkyl moiety of said aralkylester has 7-8 carbon atoms, said aralkyl moiety of said ester beingunsubstituted or substituted by at least one of sulfo, carboxyl, formyl,hydroxyl and amino.
 13. The compound as claimed in claim 1, wherein thecompound is2,3,5-trimethyl-6-[5'-(o-carboxyphenyloxycarbonyl)pentyl]-1,4-benzoquinone14. The compound as claimed in claim 1, wherein the compound is2,3,5-trimethyl-6-(5'-carboxypentyl)-1,4-benzoquinone.
 15. The compoundas claimed in claim 1, wherein the compound is2,3,5-trimethyl-6-(9'-carboxynonyl)-1,4-benzoquinone.
 16. The compoundas claimed in claim 1, wherein the compound is2,3-dimethoxy-5-methyl-6-(2'-carboxyethyl)-1,4-benzoquinone.
 17. Thecompound as claimed in claim 1, wherein the compound is2,3-dimethoxy-5-methyl-6-(9'-carboxynonyl)-1,4-benzoquinone.
 18. Thecompound as claimed in claim 1, wherein the compound is2,3,5-trimethyl-6-(5'-ethoxycarbonylpentyl)-1,4-benzoquinone.
 19. Thecompound as claimed in claim 1, wherein the compound is2,3,5-trimethyl-6-(5'-carboxy-1'-oxopentyl)-1,4-benzoquinone.
 20. Thecompound as claimed in claim 1, wherein the compound is2,3-dimethoxy-5-methyl-6-(5'-carboxy-1'-oxopentyl)-1,4-benzoquinone. 21.The compound as claimed in claim 1, wherein the compound is2,3,5-trimethyl-6-(5'-carboxy-1'-hydroxypentyl)-1,4-benzoquinone.